Cytotoxic chemotherapies have a narrow therapeutic window, with high peaks and troughs of plasma concentration. Novel nanoparticle formulations of cytotoxic chemotherapy drugs can enhance pharmacokinetic characteristics and facilitate passive targeting of drugs to tumors via the enhanced permeability and retention effect, thus mitigating toxicity. Nanoparticle vehicles currently in clinical use or undergoing clinical investigation for anticancer therapies include liposomes, polymeric micelles, protein-drug nanoparticles, and dendrimers. Multiple nanoparticle formulations of existing cytotoxic chemotherapies are approved for use in several indications, with clinical data indeed showing optimization of pharmacokinetics and different toxicity profiles compared with their parent drugs. There are also many new nanoparticle drug formulations in development and undergoing early- and late-phase clinical trials, including several that utilize active targeting or triggered release based on environmental stimuli. Here, we review the rationale for nanoparticle formulations of existing or previously investigated cytotoxic drugs, describe currently approved nanoparticle formulations of drugs, and discuss some of the most promising clinical trials currently underway.
Introduction and Rationale for Nanoparticle Reformulations
While cytotoxic chemotherapies form a cornerstone of anticancer treatment, they universally have narrow therapeutic windows. Within the last 2 decades, novel formulations of chemotherapeutics using nanoparticle vehicles have been developed to optimize pharmacokinetics and improve tumor drug targeting, mitigating toxicity while maintaining efficacy. Multiple nanoparticle chemotherapy formulations are now approved as standard therapy, and even more agents are undergoing clinical trials.
Drugs encapsulated within or conjugated to nanoparticle vehicles display pharmacokinetics that are markedly different from those of free drugs. Drug concentration after administration depends on clearance (reflecting elimination rate) and volume of distribution (reflecting the size and number of body compartments available to a drug, based on characteristics such as hydrophobicity and size).[1] Generally, by trapping cytotoxic drugs in long-circulating nanoparticles that slowly release the drug over time, the peaks and troughs of drug concentration are not as extreme as those seen with infusion of a free drug. Also, combinations of drugs can be encapsulated in a single nanoparticle to ensure combinatorial drug delivery at a defined ratio to yield a desired synergistic effect.
Additionally, trapping hydrophobic drugs like taxanes within nanoparticles with hydrophilic shells can eliminate the need for using emulsifying excipients, which have their own toxicities. These hydrophobic drugs otherwise require a vehicle of polyethoxylated castor oil (Kolliphor EL, formerly Cremophor EL)or polysorbate 80 that emulsify the water-insoluble drug and facilitate intravenous infusion. These excipients often cause hypersensitivity reactions upon infusion,[2] so reformulation to avoid their use may be beneficial. Indeed, there are case reports of successful rechallenge with nanoparticle albumin–bound (nab)-paclitaxel in patients who previously had hypersensitivity reactions to conventional paclitaxel[3]-although some patients truly do have allergic reactions to the taxane drug itself, and so there must be careful consideration of which patients may be safely rechallenged. Nevertheless, avoiding the need for these excipients may be another benefit of nanoparticle reformulations of hydrophobic drugs.
Optimizing Nanoparticle Properties to Enhance Biocompatibility
A nanoparticle vehicle must allow for sufficient duration of circulation without rapid clearance, and should facilitate passive targeting, in which the nanoparticles are preferentially deposited within tumors. To achieve this, a nanoparticle that is delivered intravenously must circulate within the blood while evading opsonization-which is nonspecific binding by plasma proteins, complement, or immunoglobulins that directs the bound particles to phagocytosis and clearance by the reticuloendothelial system (RES) of macrophages within the liver and spleen. The nanoparticles then need to successfully exit the intravascular space and enter the intratumoral extravascular space, where they must diffuse to the cancer cells, undergo internalization, and release their chemotherapy payload.[4] The key factors that affect these capabilities include nanoparticle size and surface charge.
The size of nanoparticles determines their biodistribution, since particles of different sizes have differing abilities to evade clearance by the kidneys or by the RES. For example, particles smaller than 5 nm are rapidly filtered out by the kidneys, while particles over 200 nm accumulate within the spleen, liver, and lung.[4] Additionally, nanoparticle vehicles passively target tumors rather than normal tissues because their size limits nonspecific extravasation. Tumors have leaky blood vessels with increased vascular permeability, mediated by high intratumoral levels of vascular endothelial growth factor (VEGF), nitric oxide, and other inflammatory mediators.[5,6] Nanoparticles are unable to exit the intravascular space in normal tissues, limiting their volume of distribution, but they are able to readily extravasate out of leaky tumor-associated vessels.[6] This enhanced permeability and retention (EPR) effect thus passively targets tumors while decreasing drug delivery to nontarget tissues. Consequently, nanoparticle vehicles should have sizes under 200 nm to avoid clearance by the RES while still being able to take advantage of the EPR effect. However, the EPR effect requires the presence of aberrant tumor blood vessels and thus depends on the degree of vascularity and endothelial fenestration. Moreover, the EPR effect is modulated by treatment with antiangiogenic therapy, which normalizes tumor blood vessels but may decrease this tumor-specific vessel leakiness. Indeed, following antiangiogenic therapy, intratumoral penetration of larger nanoparticles (over 100 nm) decreased, while the penetration of smaller (12-nm) nanoparticles improved.[7] The clinical utility of the effect of previous or concomitant anti-angiogenic therapies with nanoparticle chemotherapy formulations is an area of ongoing investigation.
Additionally, stromal components and interstitial fluid pressure within the tumor affect drug accumulation and diffusion. The interstitial fluid pressure within a tumor is uniformly elevated due to the generalized increased extravasation of fluids from the leaky vasculature and poor lymphatic drainage, and intratumoral drug transport thus occurs slowly, via diffusion.[5] While decreased lymphatic drainage contributes to intratumoral nanoparticle retention, the stromal extracellular matrix can also restrict diffusion of nanoparticles. In pancreatic cancers, which have dense, fibrotic stroma, only 30-nm nanoparticles could penetrate beyond the immediate perivascular space.[8] These tumor-specific characteristics likely help explain the differing efficacies of various nanoparticle chemotherapy formulations in different cancer types. Also, therapies that modulate the tumor microenvironment, such as recombinant human hyaluronidase, are likely to affect nanoparticle and drug diffusion through the stroma, and combinatorial or sequential treatment approaches continue to undergo investigation (for example, ClinicalTrials.gov identifier NCT02715804).
The surface charge of nanoparticles, called zeta potential, also impacts nanoparticle distribution and uptake. Cationic particles bind more avidly to negatively charged plasma proteins like albumin or complement proteins, and are consequently readily cleared by the RES; they thus have lower circulating duration and insufficient tumor deposition.[9] Therefore, in vivo tumor deposition of nanoparticles is optimal with slightly anionic particles that measure 150 nm in diameter,[10] and it is common to modify the surface characteristics of the nanoparticles by attaching polymer chains that confer more favorable properties. Polyethylene glycol (PEG) is a hydrophilic polymer that has a near-neutral charge, and decorating the surface of a nanoparticle with PEG moieties (pegylation) masks the surface charge to improve circulating half-life while hiding potentially antigenic epitopes and thus preventing immunologic reaction.[11] PEG polymers are also directly conjugated to drugs to optimize pharmacokinetics for clinical use, as in the cases of filgrastim, interferon alfa-2b, and asparaginase. Pegylation is an important method of conferring “stealth” properties on nanoparticles to improve the duration of their circulation. The addition of other epitopes to facilitate molecularly directed targeting and to aid in shielding the nanoparticles from macrophages and immunoglobulins is also undergoing investigation.
Nanoparticle Platforms
Several nanoparticle platforms are currently in clinical use or are being investigated for use in cancer therapeutics (Figure). Liposomes are among the most commonly used vehicles, and most of the currently approved nanoparticle chemotherapy formulations are liposomal. Liposomes are comprised of a phospholipid bilayer, with cholesterol added for bilayer stabilization, surrounding an aqueous core. The lipid envelope is in a more permeable fluid state if the environmental temperature exceeds the melting temperature, and assumes a less permeable gel state at lower temperatures; therefore, an appropriate phospholipid composition with a melting temperature higher than body temperature is required to minimize nonspecific drug leakage from the liposomes. Hydrophobic drugs can be loaded within the lipid bilayer of the liposome, whereas hydrophilic drugs remain within the aqueous core.[12]
Polymeric micelles consist of amphiphilic block polymers with a hydrophilic segment, often comprised of PEG, and a hydrophobic core; they consequently self-assemble into monolayer micelles. To increase stability and prevent overly rapid degradation and drug release, the polymers include moieties that are readily cross-linked-either within the hydrophilic region to form shell cross-linked micelles, or within the hydrophobic region to form core cross-linked micelles. Drugs can be either covalently linked to the polymers or physically trapped within the polymeric micelles, and drug release from the micelle occurs as the polymers degrade.[13]
Additionally, the binding of chemotherapeutic drugs to proteins such as albumin has also facilitated the formation of nanoparticles. Drugs that are otherwise hydrophobic, such as paclitaxel, are rendered soluble in aqueous solutions through nanoparticle albumin binding, lessening the need for excipients such as polyethoxylated castor oil, while taking advantage of the EPR effect and of mechanisms of albumin transport across endothelial cells and uptake into tumor cells.[14] Currently, nab-paclitaxel is the only compound in this class that has been approved by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), although others are in development.
Finally, dendrimers are nanoparticles formed from repetitively branched polymers arising from a core. Dendrimers are symmetric and uniform in size, and because of their branched structures, they have a multitude of covalent binding sites at the nanoparticle surface. These sites can link to drugs, targeting antibodies, or to PEG in order to favorably modify the dendrimer surface properties to avoid uptake by the RES and to minimize nonspecific cell membrane toxicity.[15] No dendrimer-bound chemotherapy formulations are currently approved, although clinical trials are underway.
Safety Considerations With Nanoparticle Therapies
The lipids and polymers utilized in nanoparticles currently in clinical use are generally accepted as being biocompatible and safe. However, novel nanoparticle vehicles must be evaluated for potential toxicity, since materials may have markedly different physicochemical characteristics when they are nanoparticle-sized; they thus may have very different effects on living cells than do their larger-sized versions, and can potentially result in toxicities even at low cumulative doses.[16] For example, nonpegylated cationic vehicles cause general cell toxicity and increased genotoxicity in vivo.[17] Also, early generations of dendrimers demonstrated unacceptable pulmonary, hematologic, and other toxicities in preclinical studies, although these toxicities can be eliminated by using more biocompatible polymers and by pegylation.[15] The potential for adverse events and toxicities related to the nanoparticle vehicle itself must be considered, especially when conducting early-phase clinical studies of nanoparticle formulations.
Liposomal vehicles may increase the risk of a hypersensitivity response, similar to what is sometimes seen with excipients such as polyethoxylated castor oil, due to a non–immunoglobulin E–mediated reaction, called complement activation–related pseudoallergy (CARPA).[18] This complement activation triggers mast cell degranulation in a subset of patients.[18,19] Properties of the liposomal nanoparticles and of the specific encapsulated drugs determine the likelihood of CARPA for a given therapeutic, with high negative surface charge and nonspherical particle shape contributing to higher rates of CARPA. For example, the loading of doxorubicin into liposomes caused deformation of the liposomes into an ellipsoid shape rather than a spherical shape, which contributed to greater rates of complement deposition and activation and higher rates of hypersensitivity reactions with pegylated liposomal doxorubicin.[19] For drugs whose liposomal formulations confer an increased risk of mild hypersensitivity reactions compared with their conventional formulations-as is the case with doxorubicin-the increased risk must be outweighed by decreases in other severe toxicities, such as cardiotoxicity, when the liposomal formulation is used. These factors remain important considerations for liposomal drugs.
Also, though PEG is generally thought to be immunologically inert, emerging evidence suggests there may be an anti-PEG immunologic reaction in subgroups of patients. Neutralizing anti-PEG antibodies have been identified in small studies in 7% to 42% of normal human subjects, which may be attributable to the widespread use of PEG in many household consumer products.[20] Small studies have also suggested an association between the presence of anti-PEG antibodies and decreased efficacy of pegasparaginase and PEG-uricase.[20] There are also case reports of immediate and delayed hypersensitivity reactions to PEG.[21] Given the importance of pegylation in making nanoparticles and other drugs more biocompatible, the clinical relevance of these antibodies needs to be further investigated.
Current Approved Nanoparticle Anticancer Therapies
A variety of nanoparticle formulations of chemotherapies have been approved by the FDA and/or EMA for treatment of a range of cancers (Table 1). Key properties and studies of these nanoparticle formulations are described below.
Liposomal anthracycline formulations
Pegylated liposomal doxorubicin and liposomal daunorubicin are available in the United States. Additionally, nonpegylated liposomal doxorubicin is approved in Europe. Both pegylated and nonpegylated liposomal doxorubicin have lower rates of cardiotoxicity than conventional doxorubicin, although they have other unique toxicities. For example, in a randomized controlled trial of patients with metastatic breast cancer, those treated with conventional doxorubicin had a significantly higher rate of cardiotoxicity (hazard ratio [HR], 3.16; 95% CI, 1.58–6.31) and significantly higher rates of alopecia, nausea, vomiting, and neutropenia, while those who received pegylated liposomal doxorubicin were more likely to have palmar-plantar erythrodysesthesia (PPE), stomatitis, and mucositis.[22] A meta-analysis of nine randomized controlled trials of pegylated or nonpegylated liposomal anthracyclines compared with conventional anthracyclines also found a significantly lower rate of cardiomyopathy with the liposomal formulations (odds ratio [OR], 0.34; 95% CI, 0.24–0.47),[23] likely due to the nano-size of the liposomal anthracycline formulations, which prevented extravasation within cardiac tissue and limited the exposure of cardiomyocytes to the treatment drug.[24] Since cardiotoxicity is associated with higher peak plasma levels of doxorubicin, liposomal formulations may blunt the incidence of cardiotoxicity by controlling drug release and thus attenuating peak plasma levels. However, there is no evidence that liposomal daunorubicin causes less cardiotoxicity than conventional daunorubicin; liposomal daunorubicin has been shown to induce clinically significant rates of cardiotoxicity.[25]
The increased rate of PPE with pegylated liposomal doxorubicin is also thought to be due to the different biodistribution and release kinetics of the drug that result from the liposomal vehicle, although this effect is not observed with nonpegylated liposomal formulations. Pegylated liposomal doxorubicin has a greater rate of deposition within the skin.[26] Also, because the nonpegylated liposomal formulation releases 90% of its doxorubicin payload within 24 hours, while the pegylated liposomal formulation releases less than 10% within 24 hours,[24] there is more drug remaining to be released from the pegylated liposomes that are deposited within the skin, and this results in more toxicity.
Despite their different toxicity profiles, liposomal formulations of anthracyclines do not necessarily demonstrate greater efficacy than comparable doses of conventional anthracyclines. A phase III, noninferiority, randomized controlled trial of pegylated liposomal doxorubicin vs conventional doxorubicin as first-line treatment in 509 women with metastatic breast cancer showed noninferiority of pegylated liposomal doxorubicin with respect to the endpoint of progression-free survival (PFS) (HR, 1.00; 95% CI, 0.82–1.22).[22]
Vincristine sulfate liposome injection (VSLI)
VSLI is a sphingomyelin/cholesterol liposomal formulation of vincristine sulfate that allows for optimized pharmacokinetics as compared with conventional vincristine. After VSLI infusion, there is a 3- to 12-hour delay in plasma clearance, contributing to an increased area under the curve (AUC) compared with conventional vincristine.[27] Thus, VSLI can be dosed more intensively (2.25 mg/m2) than conventional vincristine (1.4 mg/m2, with the dose capped at 2 mg to mitigate excessive neuropathy). In a multinational, single-arm, open-label, phase II clinical trial of 65 adults with heavily pretreated relapsed Philadelphia chromosome–negative acute lymphoblastic leukemia, including prior therapy with standard vincristine, treatment with VSLI monotherapy resulted in an impressive 20% rate of complete response or complete response with incomplete hematologic recovery (95% CI, 11.1%–31.8%).[28] Although 77% of subjects had baseline neuropathy-related signs or symptoms, only 23% of subjects had grade 3 peripheral neuropathy–related adverse events, and 1.5% had grade 4 peripheral neuropathy–related events. Subjects treated with VSLI received 1.57 to 2.76 times the standard 2-mg maximum vincristine dose, which may have contributed to overcoming relative vincristine resistance.[28] VSLI is undergoing clinical trials in a range of other hematologic malignancies.
Nanoliposomal irinotecan
Treatment with nanoliposomal irinotecan results in greater tumoral levels of irinotecan and its active metabolite, SN-38.[29] In the phase III, randomized, open-label NAPOLI-1 clinical trial, 417 patients who previously received gemcitabine-based chemotherapy for metastatic pancreatic adenocarcinoma were randomized to receive fluorouracil and folinic acid either with or without nanoliposomal irinotecan, and subjects who received the combination with nanoliposomal irinotecan had superior overall survival (OS) (HR, 0.67; 95% CI, 0.49–0.92) compared with those who did not receive the combination.[30] Nanoliposomal irinotecan is currently in additional clinical trials with combination chemotherapy, primarily in gastrointestinal cancers.
Liposomal cytarabine for intrathecal therapy of lymphomatous meningitis
Liposomal cytarabine is administered intrathecally to facilitate sustained release of the antimetabolite cytarabine in the treatment of lymphomatous meningitis, allowing for persistence of therapeutic cytarabine concentrations in the cerebrospinal fluid (CSF) for 2 weeks.[31] The vehicle is a nonpegylated liposome matrix comprised of lipid-based particles with multiple vesicles, with each vesicle having an aqueous drug-loaded core and bounded by a lipid bilayer; the aggregate particle size is 3 µm to 30 µm.[31] Slow degradation of the vehicle allows for controlled release of the encapsulated cytarabine. In a randomized, multicenter, open-label phase II trial of 28 patients with lymphoma with positive CSF cytology, the cohort treated with intrathecal cytarabine liposome injections had a response rate-defined as CSF cytology conversion from positive to negative while remaining clinically neurologically stable-that was significantly higher than that of the cohort treated with conventional intrathecal cytarabine (71% vs 15%, respectively, by intention-to-treat analysis; P = .006).[32] Because of the more prolonged duration of cytarabine exposure within the CSF with liposomal cytarabine therapy, there were higher rates of headache (27% of liposomal cytarabine cycles vs 2% of conventional cytarabine cycles) and arachnoiditis (22% of liposomal cytarabine cycles vs 13% of conventional cytarabine cycles) compared with conventional cytarabine, although most of these events were grade 1/2.[32] Concomitant administration of oral dexamethasone is recommended for arachnoiditis prophylaxis. However, cytarabine liposomal injection could not be administered concomitantly with systemic chemotherapy for central nervous system prophylaxis because of significant neurotoxicity.[33]
Nab-paclitaxel
Nab-paclitaxel is the only current FDA- and EMA-approved therapy using nanoparticle albumin-bound particles. Besides achieving passive targeting by virtue of nanoparticle size, nab-paclitaxel may take advantage of its bound albumin protein to facilitate drug transport and targeting. Nab-paclitaxel binds to endothelial cells 9.9-fold more than conventional paclitaxel and has 4.2-fold higher transport across an endothelial cell monolayer, likely by taking advantage of normal caveolin-1–mediated mechanisms of albumin transcytosis.[14] Additionally, some cancers, notably KRAS-mutant pancreatic and other cancers, demonstrate dependency on increased macropinocytosis of extracellular protein-containing fluid to obtain macromolecules needed in biosynthesis, and the efficacy of nab-paclitaxel in pancreatic cancer has been postulated to be partially attributable to increased internalization of albumin-bound paclitaxel.[34] It had also previously been thought that expression of secreted protein acidic and rich in cysteine (SPARC), also called osteonectin, a protein that is often overexpressed in the tumor extracellular matrix and that avidly binds albumin, might be associated with nab-paclitaxel benefit. However, analysis of tumor tissue from the pivotal phase III trial of nab-paclitaxel and gemcitabine in metastatic pancreatic cancer found that stromal SPARC expression was not associated with OS (HR, 1.019; P = .903),[35] and SPARC also was found not to be associated with pathologic complete response (pCR) rate in breast cancers treated neoadjuvantly with nab-paclitaxel (adjusted OR, 1.21; P = .34).[36] Thus, biomarkers capable of indicating which patients are most likely to benefit from nab-paclitaxel remain unclear.
Data are mixed regarding whether nab-paclitaxel is more effective than conventional paclitaxel. In the German Breast Group’s GeparSepto phase III randomized clinical trial in breast cancer, neoadjuvant weekly nab-paclitaxel was significantly more likely than weekly conventional paclitaxel to yield a pCR when given in sequential therapy consisting of a taxane followed by epirubicin and cyclophosphamide (adjusted OR, 1.59; 95% CI, 1.20–2.11).[36] However, these results conflict with results from the Evaluating Treatment with Neoadjuvant Abraxane (ETNA) trial in human epidermal growth factor receptor 2 (HER2)-negative breast cancer, in which neoadjuvant nab-paclitaxel did not significantly improve the pCR rate compared with conventional paclitaxel when followed by an anthracycline-based regimen (OR, 1.30; 95% CI, 0.88–1.92).[37] The role of nab-paclitaxel in neoadjuvant therapy of breast cancer remains unclear and is investigational at this point. Additionally, in the first-line treatment of metastatic breast cancer, in combination with bevacizumab, nab-paclitaxel trended toward an inferior PFS rate compared with conventional paclitaxel (HR, 1.20; 95% CI, 1.00–1.45).[38] On the other hand, administering first-line nab-paclitaxel rather than paclitaxel in combination with carboplatin in metastatic non–small-cell lung cancer significantly improved the response rate (RR) (RR ratio, 1.313; 95% CI, 1.082–1.593),[39] and nab-paclitaxel in combination with gemcitabine had efficacy in metastatic pancreatic cancer, while conventional paclitaxel showed little evidence of efficacy in that setting.[40] Thus, in some cancers, nab-paclitaxel appears to show hints of greater efficacy through improvements in pCR rate or RR; however, improvement in survival compared with conventional paclitaxel remains undemonstrated.
Novel Nanoparticle Formulations of Cytotoxics
Table 2 lists selected novel nanoparticle therapeutics currently undergoing clinical trials, and we further describe selected therapies below.
CPX-351 is a liposomal formulation of cytarabine and daunorubicin at a 5:1 molar ratio. This fixed molar ratio of cytarabine and daunorubicin persisted on pharmacokinetic analyses for 24 hours after the final dose, and pharmacokinetic studies showed cytarabine half-life was 38 to 64 hours, compared with 3 hours for conventional cytarabine.[41] CPX-351 improved OS compared with standard chemotherapy with cytarabine and daunorubicin in a randomized controlled phase III clinical trial of older adults with secondary acute myeloid leukemia (HR, 0.69; P = .005), although with similar rates of grade 3–5 adverse events.[42] Given the positive phase III trial results, rolling submission of a New Drug Application was initiated in October 2016 and is expected to be completed in early 2017. Additional clinical trials of CPX-351 are ongoing, as described in Table 2.
The first dendrimer-bound cytotoxic nanoparticle to proceed into clinical trials is DTX-SPL8783 (dendrimer-docetaxel). The dendrimer is comprised of polylysine branched polymers, with additional PEG moieties linked to the surface.[43] Dendrimer-docetaxel is undergoing a phase I clinical trial in Australia. Additionally, the dendrimer platform may facilitate the binding of antibody epitopes to the surface, making active targeting possible in the future.
Several nanoparticle formulations now in development include various methods of active targeting to further improve tumoral drug delivery. Anti–epidermal growth factor receptor (EGFR) immunoliposomes are comprised of pegylated liposomes conjugated to antigen-binding fragments of the anti-EGFR antibody cetuximab. A phase I clinical trial of anti-EGFR immunoliposomes loaded with doxorubicin in patients with EGFR-overexpressing solid tumors found no patients had PPE, alopecia, or cardiotoxicity.[44] Thus, these actively targeted immunoliposomes may further improve drug delivery over what is possible with pegylated liposomal doxorubicin, and a phase II trial is planned in metastatic EGFR-expressing triple-negative breast cancer. Analogously, MM-302 is a doxorubicin-loaded pegylated liposome conjugated to an anti-HER2 antibody.[45] A phase II/III clinical trial is ongoing in patients with HER2-amplified breast cancer refractory to existing standard HER2-targeted therapies.
Additionally, vehicles can be engineered to become more porous, thereby increasing drug release under certain environmental conditions, such as high temperature or low pH. Lysolipid-thermosensitive liposomal doxorubicin (LTLD) has a pegylated liposomal vehicle that includes surfactant molecules within the phospholipid bilayer to stabilize pores that form around the melting temperature at 39–42°C.[46] Therapeutically inducing hyperthermia to these temperatures by radiofrequency ablation, high-intensity focused ultrasound, or (for tumors very close to the skin surface) superficial warming results in a marked increase in doxorubicin release-to 80% within 20 seconds.[46] LTLD is now undergoing evaluation in a randomized phase III trial of radiofrequency ablation with either LTLD or placebo in patients with hepatocellular carcinoma, and is also undergoing early-phase clinical trials for other indications. Vehicles can also be engineered to release drug in acidic environments, such as inside acidified endosomes and lysosomes, where compounds that undergo endocytosis end up. NC-6300 is a polymeric micelle conjugated to epirubicin, and the polymers comprising the micelle are covalently linked using acid-sensitive linkages that are cleaved in low-pH environments. Epirubicin release is indeed pH-dependent, with 80% of drug released within 1 hour at an acidic pH of 3, while only 20% of drug is released within 24 hours at a neutral pH of 7.4.[47] NC-6300 is undergoing clinical trials in Japan.
KEY POINTS
- Nanoparticle formulations of existing cytotoxic therapies alter pharmacokinetic properties and enhance passive tumor targeting via the enhanced permeability and retention effect, thus changing toxicity profiles and drug distribution.
- The majority of already approved nanoparticle formulations have liposomal vehicles, but protein-drug nanoparticles, polymeric micelles, and dendrimers are also platforms undergoing clinical evaluation.
- Future applications of nanoparticle drug delivery, while still undergoing development, include active molecular tumor targeting, environment-sensitive drug release, and delivery of novel therapeutic nucleic acids.
Finally, although not the primary focus of this review, nanoparticle vehicles are also used to facilitate cellular delivery of novel potential therapeutic agents, including small interfering RNAs that can silence key oncogenes and DNA plasmids that can restore expression of lost tumor suppressors.[48] Selected compounds in this category that are currently in clinical trials are listed in Table 2.
Unfortunately, several nanoparticle formulations with intriguing early-phase clinical trial results failed to demonstrate efficacy in larger trials. A notable example is BIND-014, comprised of docetaxel encapsulated within polymeric micelles conjugated with ligands targeting prostate-specific membrane antigen, which is expressed in prostate cancer cells and on tumor vasculature in a variety of cancers. BIND-014 preliminarily demonstrated activity in phase I trials,[49] but failed in phase II clinical trials in several types of advanced cancer and is not undergoing further development.[50] CRLX101 is a conjugate of the chemotherapeutic camptothecin and cyclodextrin-PEG polymers, but CRLX101 combined with bevacizumab failed to demonstrate improvement in PFS compared with physician’s choice of standard therapy in a randomized phase II clinical trial in refractory metastatic renal cell carcinoma.[51] Although CRLX101 continues to be studied in other settings, this failure was a major setback. These failures, and those of preceding clinical candidates, highlight the pitfalls of clinical development of these drugs. Many nanoparticle formulations use existing FDA-approved single-agent chemotherapeutics, such as docetaxel, and the clinical benefits of a novel reformulation would need to be sufficient to justify approval. Since there have been so few examples of superior efficacy of a nanoparticle formulation over the parent drug, thoughtful clinical trial design is necessary to identify indications in which a nanoparticle formulation can add substantially to the existing standard of care rather than simply replace the parent drug. Additionally, running single-arm phase II clinical trials makes study results more difficult to interpret, since there are confounding factors that impede comparison with historical controls. While nanoparticle formulations are clearly important technologic advances with tremendous promise, the clinical trials to demonstrate efficacy must be carefully designed.
Conclusion
Nanoparticle formulations of cytotoxic therapies facilitate optimization of pharmacokinetics and patterns of distribution via the EPR effect, resulting in mitigation of toxicities and passive targeting of drugs to tumors. Several of these formulations are now approved in a range of cancer types, and many other formulations are currently undergoing clinical trials. While clinical studies have clearly shown important benefits-such as reductions in key toxicities (eg, the cardiotoxicity associated with doxorubicin and the neuropathy associated with vincristine) while maintaining dose intensity-there has been a dearth of strong evidence demonstrating superior efficacy of nanoparticle chemotherapy formulations compared with the conventional chemotherapy formulations, although CPX-351 may be one notable exception. Many of the formulations currently in clinical trials utilize active targeting or triggered release in response to an environmental stimulus to further improve drug localization to desired tumor sites. Nanoparticle vehicles also have the potential to deliver completely new classes of therapy, such as nucleic acids, that otherwise have significant barriers to efficient delivery.
Financial Disclosure: The authors have no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
References:
1. Katzung BG, Masters SB, Trevor AJ, editors. Basic and clinical pharmacology. McGraw-Hill Medical. 2012.
2. Weiss RB, Donehower RC, Wiernik PH, et al. Hypersensitivity reactions from taxol. J Clin Oncol. 1990;8:1263-8.
3. Fader AN, Rose PG. Abraxane for the treatment of gynecologic cancer patients with severe hypersensitivity reactions to paclitaxel. Int J Gynecol Cancer. 2009;19:1281-3.
4. Blanco E, Shen H, Ferrari M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat Biotechnol. 2015;33:941-51.
5. Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31:2205-18.
6. Maeda H, Nakamura H, Fang J. The EPR effect for macromolecular drug delivery to solid tumors: improvement of tumor uptake, lowering of systemic toxicity, and distinct tumor imaging in vivo. Adv Drug Deliv Rev. 2013;65:71-9.
7. Chauhan VP, Stylianopoulos T, Martin JD, et al. Normalization of tumour blood vessels improves the delivery of nanomedicines in a size-dependent manner. Nat Nanotechnol. 2012;7:383-8.
8. Cabral H, Matsumoto Y, Mizuno K, et al. Accumulation of sub-100 nm polymeric micelles in poorly permeable tumours depends on size. Nat Nanotechnol. 2011;6:815-23.
9. Chauhan VP, Jain RK. Strategies for advancing cancer nanomedicine. Nat Mater. 2013;12:958-62.
10. He C, Hu Y, Yin L, et al. Effects of particle size and surface charge on cellular uptake and biodistribution of polymeric nanoparticles. Biomaterials. 2010;31:3657-66.
11. Caliceti P, Veronese FM. Pharmacokinetic and biodistribution properties of poly(ethylene glycol)-protein conjugates. Adv Drug Deliv Rev. 2003;55:1261-77.
12. Pattni BS, Chupin VV, Torchilin VP. New developments in liposomal drug delivery. Chem Rev. 2015;115:10938-66.
13. Kedar U, Phutane P, Shidhaye S, Kadam V. Advances in polymeric micelles for drug delivery and tumor targeting. Nanomedicine. 2010;6:714-29.
14. Desai N, Trieu V, Yao Z, et al. Increased antitumor activity, intratumor paclitaxel concentrations, and endothelial cell transport of cremophor-free, albumin-bound paclitaxel, ABI-007, compared with cremophor-based paclitaxel. Clin Cancer Res. 2006;12:1317-24.
15. Jain K, Kesharwani P, Gupta U, Jain NK. Dendrimer toxicity: Let’s meet the challenge. Int J Pharm. 2010;394:122-42.
16. Nel A, Xia T, Madler L, Li N. Toxic potential of materials at the nanolevel. Science. 2006;311:622-7.
17. Knudsen KB, Northeved H, Kumar PE, et al. In vivo toxicity of cationic micelles and liposomes. Nanomedicine. 2015;11:467-77.
18. Szebeni J. Complement activation-related pseudoallergy: a new class of drug-induced acute immune toxicity. Toxicology. 2005;216:106-21.
19. Szebeni J, Bedocs P, Rozsnyay Z, et al. Liposome-induced complement activation and related cardiopulmonary distress in pigs: factors promoting reactogenicity of Doxil and AmBisome. Nanomedicine. 2012;8:176-84.
20. Yang Q, Lai SK. Anti-PEG immunity: emergence, characteristics, and unaddressed questions. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2015;7:655-77.
21. Wenande E, Garvey LH. Immediate-type hypersensitivity to polyethylene glycols: a review. Clin Exp Allergy. 2016;46:907-22.
22. O’Brien ME, Wigler N, Inbar M, et al. Reduced cardiotoxicity and comparable efficacy in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil) versus conventional doxorubicin for first-line treatment of metastatic breast cancer. Ann Oncol. 2004;15:440-9.
23. Rafiyath SM, Rasul M, Lee B, et al. Comparison of safety and toxicity of liposomal doxorubicin vs. conventional anthracyclines: a meta-analysis. Exp Hematol Oncol. 2012;1:10.
24. Waterhouse DN, Tardi PG, Mayer LD, Bally MB. A comparison of liposomal formulations of doxorubicin with drug administered in free form: changing toxicity profiles. Drug Saf. 2001;24:903-20.
25. Lowis S, Lewis I, Elsworth A, et al. A phase I study of intravenous liposomal daunorubicin (DaunoXome) in paediatric patients with relapsed or resistant solid tumours. Br J Cancer. 2006;95:571-80.
26. Lorusso D, Di Stefano A, Carone V, et al. Pegylated liposomal doxorubicin-related palmar-plantar erythrodysesthesia (‘hand-foot’ syndrome). Ann Oncol. 2007;18:1159-64.
27. Silverman JA, Deitcher SR. Marqibo(R) (vincristine sulfate liposome injection) improves the pharmacokinetics and pharmacodynamics of vincristine. Cancer Chemother Pharmacol. 2013;71:555-64.
28. O’Brien S, Schiller G, Lister J, et al. High-dose vincristine sulfate liposome injection for advanced, relapsed, and refractory adult Philadelphia chromosome-negative acute lymphoblastic leukemia. J Clin Oncol. 2013;31:676-83.
29. Kalra AV, Kim J, Klinz SG, et al. Preclinical activity of nanoliposomal irinotecan is governed by tumor deposition and intratumor prodrug conversion. Cancer Res. 2014;74:7003-13.
30. Wang-Gillam A, Li CP, Bodoky G, et al. Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial. Lancet. 2016;387:545-57.
31. Murry DJ, Blaney SM. Clinical pharmacology of encapsulated sustained-release cytarabine. Ann Pharmacother. 2000;34:1173-8.
32. Glantz MJ, LaFollette S, Jaeckle KA, et al. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis. J Clin Oncol. 1999;17:3110-6.
33. Jabbour E, O’Brien S, Kantarjian H, et al. Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia. Blood. 2007;109:3214-8.
34. White E. Exploiting the bad eating habits of Ras-driven cancers. Genes Dev. 2013;27:2065-71.
35. Hidalgo M, Plaza C, Musteanu M, et al. SPARC expression did not predict efficacy of nab-paclitaxel plus gemcitabine or gemcitabine alone for metastatic pancreatic cancer in an exploratory analysis of the phase III MPACT trial. Clin Cancer Res. 2015;21:4811-8.
36. Untch M, Jackisch C, Schneeweiss A, et al. Nab-paclitaxel versus solvent-based paclitaxel in neoadjuvant chemotherapy for early breast cancer (GeparSepto-GBG 69): a randomised, phase 3 trial. Lancet Oncol. 2016;17:345-56.
37. Gianni L, Mansutti M, Anton A, et al. ETNA (Evaluating Treatment with Neoadjuvant Abraxane) randomized phase III study comparing neoadjuvant nab-paclitaxel (nab-P) versus paclitaxel (P) both followed by anthracycline regimens in women with HER2-negative high-risk breast cancer: a MICHELANGO study. J Clin Oncol. 2016;34(suppl):abstr 502.
38. Rugo HS, Barry WT, Moreno-Aspitia A, et al. Randomized phase III trial of paclitaxel once per week compared with nanoparticle albumin-bound nab-paclitaxel once per week or ixabepilone with bevacizumab as first-line chemotherapy for locally recurrent or metastatic breast cancer: CALGB 40502/NCCTG N063H (Alliance). J Clin Oncol. 2015;33:2361-9.
39. Socinski MA, Bondarenko I, Karaseva NA, et al. Weekly nab-paclitaxel in combination with carboplatin versus solvent-based paclitaxel plus carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer: final results of a phase III trial. J Clin Oncol. 2012;30:2055-62.
40. Ma WW, Hidalgo M. The winning formulation: the development of paclitaxel in pancreatic cancer. Clin Cancer Res. 2013;19:5572-9.
41. Feldman EJ, Lancet JE, Kolitz JE, et al. First-in-man study of CPX-351: a liposomal carrier containing cytarabine and daunorubicin in a fixed 5:1 molar ratio for the treatment of relapsed and refractory acute myeloid leukemia. J Clin Oncol. 2011;29:979-85.
42. Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of VYXEOS (CPX-351) versus 7+3 in older patients with newly diagnosed high-risk (secondary) AML. J Clin Oncol. 2016;34(suppl):abstr 7000.
43. Kesharwani P, Iyer AK. Recent advances in dendrimer-based nanovectors for tumor-targeted drug and gene delivery. Drug Discov Today. 2015;20:536-47.
44. Mamot C, Ritschard R, Wicki A, et al. Tolerability, safety, pharmacokinetics, and efficacy of doxorubicin-loaded anti-EGFR immunoliposomes in advanced solid tumours: a phase 1 dose-escalation study. Lancet Oncol. 2012;13:1234-41.
45. Espelin CW, Leonard SC, Geretti E, et al. Dual HER2 targeting with trastuzumab and liposomal-encapsulated doxorubicin (MM-302) demonstrates synergistic antitumor activity in breast and gastric cancer. Cancer Res. 2016;76:1517-27.
46. Kneidl B, Peller M, Winter G, et al. Thermosensitive liposomal drug delivery systems: state of the art review. Int J Nanomedicine. 2014;9:4387-98.
47. Harada M, Bobe I, Saito H, et al. Improved anti-tumor activity of stabilized anthracycline polymeric micelle formulation, NC-6300. Cancer Sci. 2011;102:192-9.
48. Chen J, Guo Z, Tian H, Chen X. Production and clinical development of nanoparticles for gene delivery. Mol Ther Methods Clin Dev. 2016;3:16023.
49. Von Hoff DD, Mita MM, Ramanathan RK, et al. Phase I study of PSMA-targeted docetaxel-containing nanoparticle BIND-014 in patients with advanced solid tumors. Clin Cancer Res. 2016;22:3157-63.
50. Ledford H. Bankruptcy filing worries developers of nanoparticle cancer drugs. Nature. 2016;533:304-5.
51. Voss M, Hutson T, Hussain A, et al. A randomized phase 2 trial of CRLX101 in combination with bevacizumab in patients with metastatic renal cell carcinoma (mRCC) vs standard of care. BJU Intl. 2016;118(suppl S5)5.
